Detailed revision notes from lecture course on cancer taught by Dr Khaled, University of Cambridge, with additional reading and insights from key publications summarised.
Cancer Therapeutics
Dr Walid Khaled
wtk22@cam.ac.uk
Lectures Outline
Lecture 1: The molecular complexity of cancer
Lecture 2: Heterogeneity of tumours
Lecture 3: How to kill a cancer cell?
Lecture 4: Personalized medicine and pharmacogenomics
Essays:
- Discuss the impact of inter- and intra-tumour heterogeneity on targeted cancer therapy.
- Discuss the different types of targeted cancer therapies.
- Is personalised cancer therapy possible? And what are technological requirements to
achieve this?
- Discuss how immunotherapy is revolutionising cancer treatment.
- Discuss how new sequencing technologies are changing cancer diagnosis and treatment.
2018 (Paper 3) Discuss how immunotherapy is revolutionising cancer treatment.
2018 (Paper 4) Discuss how new sequencing technologies are changing cancer diagnosis and
treatment.
2017 (Paper 4) Discuss the impact of genomics on targeted cancer therapies.
2016 (Paper 4) Discuss the impact of inter- and intra-tumour heterogeneity on targeted
cancer therapies.
2015 (Paper 4) Sequencing, pharmacogenomics and Avatars: is personalised cancer therapy
possible?
2014 (Paper 1) Pharmacogenomics has the potential to revolutionize personalised cancer
therapeutics. Discuss.
Lecture 1: The molecular complexity of cancer
Introduction:
• ~12.2 million new cases of cancer a year and ~7.5 million deaths a year between
both males and females.
• The most common cancer in men is prostate cancer (25%) and in women – breast
cancer (30%).
• The most lethal cancer in both men and women is lung cancer, which accounts for
more than 20% of deaths for both genders.
What is cancer?
• Cancer is a malignant neoplastic disease, in which there is an uncontrolled
proliferation of cells typically with invasion and destruction of adjacent normal
tissue, and often with metastatic spread to distant parts of the body via lymphatic or
blood vessels.
• In majority of cases, cancers are associated with somatic mutations (that occur in
somatic cells after birth).
,• Cancer is associated with both chromosomal and microsatellite instabilities.
o Chromosomal instability (CIN) is a type of genomic instability in
which chromosomes are unstable, such that either whole chromosomes or
parts of chromosomes are duplicated or deleted.
o Microsatellite instability (MSI) is the condition of genetic hypermutability
(predisposition to mutation) that results from impaired DNA mismatch repair
(MMR). The presence of MSI represents phenotypic evidence that MMR is
not functioning normally.
• The number of driver mutations required for benign tumour to become malignant
has been determined for different cancers:
o 11 – colorectal
o 2 – kidney
o 4 – stomach
o 6 – lung
o 4 – breast
o 6 – brain
• Cancer development:
o Hyperplasia
▪ Hyperproliferation
▪ Intact morphology
o Dysplasia
▪ Morphology changes
o Carcinoma in situ
o Invasive carcinoma
▪ Invasion of surrounding tissue
o Metastasis
▪ Invasion of distant organs
• Hallmarks of cancer
o Sustained proliferative signalling
▪ acquisition of oncogenes
o Evading growth suppressors
▪ loss of tumours suppressors
o Enabling replicative immortality
▪ telomerase activation
o Inducing angiogenesis
▪ Secretion of VEGF
o Resisting cell death
loss of senescence
o Activating invasion and metastasis
▪ epithelial-mesenchymal transition
• Criticism of Hallmarks of Cancer by Hanahan and Weinberg
o These hallmarks were derived under assumption of equivalence between in
vitro and in vivo data (in transgenic mouse models and human cancer
patients).
o The complexity of cancer is not reflected
, o The relationship between control of cell proliferation and carcinogenesis
stem from the claim that “the most fundamental trait of cancer cells involves
their ability to sustain chronic proliferation”, criticised by Sonnenschein as he
points out that cells in a tumour have not been shown to proliferate at a
faster rate than normal enterocytes or blastomeres. Instead suggests that
cancer is the defect of tissue-architecture and that proliferation and motility
are default state of all cells. A highly contested opinion because contradicts
to what is known about behaviour of cells in culture, yet indeed in vitro
models are not physiologically representative.
Sustained Cell Growth
a. Proto-oncogenes encode genes that promote cell proliferation
b. Oncogenes tend to be
i. Transcription factors (e.g. MYC, ETS, MITF and SOX2)
ii. Chromatin remodellers (e.g. EZH2, MBD3 and CHD4)
iii. Growth factors and their receptors (e.g. ERBB2/HER2)
iv. Signal transducers (e.g. RAS, RAF and AKT)
v. Apoptosis regulators (e.g. BCL2, BCL-XL)
vi. miRNA/lncRNA (e.g. MIR21, MIR10b, SChLAP1, HOTAIR)
vii. ceRNA (e.g. PTEN)
c. Modes of oncogene activation
i. Chromosome re-arrangement
1. May result in a strong promoter or enhancer
upstream of the oncogene, e.g. MYC due to
translocation of immunoglobulin enhancers in
malignant lymphomas
ii. Point mutation
1. KRAS, NRAS, HRAS in lung, colon and pancreatic
cancer and BRAF in melanoma
iii. Gene amplification
1. HER2 in breast cancer - more than 6 copies
iv. miRNA upregulation
1. miRNAs have been identified with both oncogene
and tumour suppressor function (downregulated in
the latter case)
2. miR21 overexpression associated with chronic
lymphocytic leukaemia, acute myeloid leukaemia,
glioblastoma, pancreatic, breast and other cancers
through transcriptional activation of PTEN, PDCD4
and TPM1. In mouse models its overexpression
induces lymphoma.
Tumour Suppressors
a. The most famous tumour suppressor is p53 (transcription factor),
which is mutated in 50% of all cancers
a. p53 is activated by DNA damage/stress and when
activated, it leads to growth arrest, apoptosis, senescence,
genomic stability and DNA repair
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